Vibrio vulnificus causes fatal septicemic and wound infections in immunocompromised humans following raw oyster consumption or exposure of open wounds to oyster-harvested waters. The capsular polysaccharide of Vibrio vulnificus (VvPS) is believed to confer the property of invasiveness. With the objective of evaluating the pathogenic and protective roles of VvPS and other protein antigens of V. vulnificus, we synthesized conjugate vaccines of carbotype 1 VvPS with TT or inactivated cytolysin or elastase of V. vulnificus by two different schemes. The immunogenicity of these conjugates was evaluated in Swiss shite mice by subcutaneous injections in saline. All conjugates elicited higher capsular antibody responses than VvPS alone and induced elevated IgG and IgM responses. The conjugates prepared through carboxyl activation of VvPS (VvPS-TTa, VvPS-cytolysin and VvPS-elastase) were more immunogenic than the one prepared through hydroxyl activation (VvPS-TTb). Capsular antibody response was significantly enhanced by concurrent intraperitoneal administration of conjugates with MPL+TDM adjuvant.The individual and synergistic protective effects of VvPS, cytolysin and elastase alone and in conjugate vaccine forms were evaluated in a mouse septicemia model. VvPS-TTa vaccine conferred protection to 80% of actively immunized mice following intraperitoneal infection with -5 LD50 of carbotype 1 V. vulnificus, while the protection conferred by VvPS- cytolysin and VvPS-elastase was 40 and 44% respectively. VvPS-TTb was least protective. Control mice immunized with VvPS, cytolysin or elastase alone, VvPS followed by cytolysin, or saline only, showed 70- 100% mortality. Thus, VvPS-TTa is highly immunogenic and protective in mice, and appears suitable for clinical evaluation. Passive protection studies using VvPS-TTa-induced antisera are underway.